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Rapid assembly of heterocycle grafted macrocycles via tandem one-pot double 1,3-dipolar cycloaddition reaction†
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R. Prasanna, S. Purushothaman and R. Raghunathan* Synthesis of triazole linked macrocycles grafted with glycospiroheterocycle was accomplished by stereoand regioselective tandem double 1,3-dipolar cycloaddition (1,3-DC) reaction. By this method we could Received 20th August 2014, Accepted 24th September 2014
construct complex chiral macrocycles in good yields from the easily available starting materials and we could achieve the synthesis of two heterocyclic rings involving simultaneous formation of five bonds in
DOI: 10.1039/c4ob01778a
one-pot reaction. The structures of the macrocycles were confirmed by spectroscopic methods and
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single crystal XRD.
Introduction The important objective in modern organic synthesis is to develop new methods for the construction of complex molecules with high synthetic efficiency.1 Multicomponent reactions (MCRs) are essentially atom economical processes in which complex heterocycles are synthesized from easily available starting materials in a facile one-pot reaction.2,3 Within this class, multicomponent 1,3-DC reaction has been widely used for the construction of biologically significant spiro-oxindole heterocyclic systems.4 Macrocycles are found to have diverse applications in supramolecular chemistry as sensors, phase-transfer catalysts, molecular pores and in drug delivery.5,6 In addition, the conformationally rigid cyclic backbone makes the macrocycles highly selective for ion recognition.7 Numerous macrocyclic compounds with biological significance are reported in the literature.8,9 A progressive interest has been directed to the chemistry of the crown ethers containing macrocycles, since, these macrocycles are found to exhibit interesting host–guest complexation.10 Isatin and its derivatives are known to be privileged scaffolds with a broad spectrum of biological properties such as anti-HIV, anti-TB activity, anticancer, antifungal and antimycobacterial, hence isatin analogs have fascinated both medicinal and synthetic chemist’s interest.11Sugar incorporated natural products forms part of important bioactive macro-
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai-600025, Tamil Nadu, India. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental details and copies of NMR spectra for all new compounds. CCDC 888096 and 888097. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ob01778a
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cycles such as erythromycin, rapamycin, vancomycin, and epothilone.12 Encouraged by the above results, we were prompted to construct hybrid glyco-conjugated isatin derived macrocycles. However, the availability of a short and efficient method for the synthesis of such macrocycles still remains a challenge.13 In our continued efforts for the construction of such molecules by efficient synthetic methods14,15 we propose to use a one-pot tandem double 1,3-dipolar cycloaddition reaction for the synthesis of heterocycle grafted sugar macrocycles. There are no previous reports in the literature on one-pot tandem double 1,3-DC reaction (“click reaction” followed by cycloaddition of azomethine ylide (AMY)).
Results and discussion We have accomplished the synthesis of glucosylspiro-pyrrolizidine grafted macrocycle 10a with a triazole linker by a one-pot double 1,3-DC reaction. The starting materials for the multicomponent reaction O-propargyl glucosyl-enone ester 3a (alkyne fragment) and N-alkyl/benzyl azido isatin 7a (azide fragment) were prepared from D-glucose and isatin respectively (Scheme 1). Synthesis of alkyne fragments 3a–b was achieved from 16 D-glucose by adopting a reported procedure (Scheme 2). The azide fragment was synthesized from isatin as shown in Scheme 3.17 Isatin 4 was reacted with 1,2-dibromoethane/ α,α′-dibromo-p-xylene 5a/5b to give N-alkyl/benzyl bromo isatin 6a/6b. The bromo compound was then converted into azide 7a/7b by treating with NaN3 in DMSO. The structure of N-alkyl/ benzyl azido isatins 7a–b was confirmed by 1H and 13C NMR spectra. Before carrying out the tandem one-pot protocol, we studied the feasibility of obtaining the macrocycles using a
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Scheme 1
Synthetic plan.
Scheme 2
Synthesis of alkyne fragments 3a–b.
Scheme 3
Synthesis of azide fragments 7a–b.
Scheme 4
Model reaction: synthesis of triazole linker 8a.
two step approach. In the first step, the O-alkynyl enone 3a and N-alkyl/benzyl azido isatin 7a were subjected to click reaction with CuSO4·5H2O and sodium ascorbate in THF–water to give 1,4-triazole 8a in good yield (Scheme 4). The structure of the compound 8a was characterized by spectroscopic methods. A neat singlet at δ 7.55 corresponding to triazole –CH– proton proved the presence of a triazole unit. In the 13C NMR spectrum of 8a the carbonyl carbons exhibited peaks at 157.1, 164.9 and 180.8 ppm. Having synthesized the N-isatinyl triazole linked glucosyl ester 8a in good yield; an intramolecular azomethine ylide
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cycloaddition reaction was performed for the synthesis of glucosylspiro-oxindolopyrrolizidine macrocycle 10a. Thus, the reaction of equimolar amounts of compound 8a and L-proline 9a in refluxing acetonitrile gave the macrocycle 10a, but the product was obtained in low yield. The yield of the product could be improved (72%) using toluene as a solvent under reflux conditions in the Dean–Stark apparatus (Scheme 5, Table 1). After confirming the formation of a macrocycle by a stepwise methodology, the tandem one-pot double 1,3-DC reaction was carried out by reacting O-propargyl enone 3a, N-alkyl azido
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Scheme 5
Table 1
Paper
Model reaction: synthesis of macrocycle 10a.
Effect of solvent on the yield of reaction
No.
Solvent
Temperature (°C)
Time (h)
Yielda (%)
1 2 3 4 5 6
Toluene Benzene CH3CN CH3OH DMF DMSO
Reflux Reflux Reflux Reflux 120 120
6 6 12 24 3 3
72 45 65 32 — —
a
Isolated yield.
isatin 7a and secondary amino acid L-proline 9a in a one-pot reaction. The reactants were subjected to ‘click’ reaction with CuI, N,N-diisopropylethylamine (DIEA) in dry CH3CN at room temperature to give the 1,4-triazoles 8a–b. TLC analysis clearly showed the completion of click reaction and the formation of a single product. The reaction mixture was then heated to reflux without isolation of 1,4-triazole. The azomethine ylide generated by secondary amino acid 9a with an N-isatinyl diketone unit reacted intramolecularly with glucosyl ester 8a to give triazole linked glucosyl spiro-oxindole pyrrolizidine macrocycle 10a in a one-pot three component reaction. This tandem methodology offers simultaneous formation of two heterocyclic rings with the formation of five bonds and a complex glucosylmacrocycle in good yields (72–76%) (Scheme 6). The methodology was extended for the synthesis of a variety of macrocycles using the enone 3b and dipoles generated from other amino acids and active ketones. The results are summarized in Table 2. Since the tandem methodo-
Scheme 6
logy required only one stage of purification, the yield of the product in the reaction is better than in a stepwise reaction. The structure and the regiochemistry of the cycloadducts 10a–f were established by spectroscopic data. In the IR spectrum of 10a, the two carbonyl groups showed peaks at 1720 and 1612 cm−1. The Ha proton resonated as a doublet at δ 3.87 (d, J = 7.2 Hz). A multiplet in the region of δ 2.95–2.99 was observed for the Hb proton. This clearly proved the regio- and stereoselectivity of the cycloaddition reaction. The presence of N-methine carbon of pyrrolizidine was confirmed by the signal at 71.2 ppm in the 13C NMR spectrum of 10a. The spiro carbon and ester carbonyl carbon exhibited peaks at 72.3 and 173.3 ppm respectively. Moreover, the cycloadduct 10a exhibited a peak at m/z 566.2611 (M+ + 1) in HRMS. Similarly, the 1H and 13C spectra for 10b–f showed signals at the expected δ values. Finally, the regio- and stereochemical outcome of the cycloaddition reaction was confirmed by a single crystal X-ray analysis of the cycloadduct 10e (Fig. 1).18 With a view to explore the potential application of the tandem methodology, similar types of reactions were carried out with the p-xylyl group as a spacer unit. Thus, the reaction between N-benzyl azido isatin 7b, O-propargyl enones 3a–b and secondary amino acids (L-proline 9a, thiazolidine-4carboxylic acid 9b and sarcosine 9c) yielded glycosyl-spiroheterocycle grafted macrocycles 11a–f in good yields (Scheme 7). The results are summarized in Table 3. The structure and the regiochemistry of all the cycloadducts 11a–f were established by spectroscopic data. The 1H and 13 C spectra for 11a–f showed signals at the expected δ values.
Tandem one-pot 1,3-DC reaction.
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Organic & Biomolecular Chemistry Tandem reaction of N-alkyl azido isatin 7a
Conclusions a
O-Alkynyl enone
Amino acid
Overall yield (%) Time Adduct (h) Stepwise Tandem 10a
24
63
76
10b
22
61
72
In conclusion, we have developed a simple and an efficient protocol for the synthesis of triazole linked glucosylspiroheterocycle grafted macrocycles through a tandem double 1,3dipolar cycloaddition methodology. Two heterocyclic units grafted to a macrocycle were synthesized with concurrent formation of five chemical bonds in this tandem double cycloaddition process.
Experimental section Published on 24 September 2014. Downloaded on 04/11/2014 17:36:41.
General considerations
a
10c
20
59
70
10d
20
61
76
10e
22
61
74
10f
22
61
71
Isolated yield.
Fig. 1 ORTEP diagram of 10e. For clarity purpose hydrogen atoms are not shown.
The regio- and stereochemical outcome of the cycloaddition reaction was confirmed by a single crystal X-ray analysis of the cycloadduct 11a.18
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Melting points were recorded in capillary tubes and are uncorrected. IR spectra were recorded on an ABB IR-MB3000 series FT-IR spectrophotometer. The 1H NMR (300, 400, 500 MHz), 13C NMR (75 MHz), DEPT, COSY and HMBC spectra were recorded on Bruker (Avance) 300 MHz, 400 MHz and 500 MHz instruments in CDCl3 using TMS as an internal standard. Chemical shifts are given in parts per million and the coupling constants are given in hertz. High resolution mass measurements were carried out using a Micromass Q-ToF instrument using direct inlet mode. Specific rotation was recorded on a RUDOLPH AUTOPOL II, Automatic Polarimeter. Single crystal X-ray diffraction analysis was performed using the Bruker Kappa APEXII area-detector diffractometer. Column chromatography was performed on silica gel (ACME, 100–200 mesh). Routine monitoring of the reaction was done using thin layer chromatography developed on glass plates coated with silica gel-G (ACME) of 25 mm thickness and visualized with iodine. Preparation of monobromo compound 6a–b. To a stirred suspension of potassium carbonate (2.76 g, 20 mmol) in dry DMF (10 ml) was added isatin 4 (1.47 g, 10 mmol), and the solution was stirred at room temperature for 30 min followed by the addition of 1,2-dibromoethane 5a (1.88 g, 10 mmol)/ α,α′-dibromo-p-xylene 5b (2.61 g, 10 mmol) in DMF at room temperature. After the completion of the reaction, as evidenced by TLC, K2CO3 was filtered off, and the solution was extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification of the reaction mixture via column chromatography using hexane–ethyl acetate (8 : 2) furnished the desired N-alkyl/ benzyl bromo isatin in good yields. Preparation of azide fragments 7a–b. To a stirred solution of 1-(2-bromoethyl) indoline-2,3-dione 6a (1 mol)/1-(4-(bromomethyl) benzyl)indoline-2,3-dione 6b (1 mol) in DMSO (60 mL) NaN3 (1.5 mol) was added. The mixture was stirred at room temperature for about 6 h (monitored by TLC). Upon completion of the reaction the mixture was washed with water and extracted with dichloromethane (4 × 20 mL). The combined organic layers were dried (MgSO4) and filtered, concentrated in a vacuum. The azides 7a–b obtained were used without further purification.
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Scheme 7
Table 3
Tandem one-pot 1,3-DC reaction.
Tandem reaction with N-benzyl azido isatin 7b
O-Alkynyl enone
a
Paper
Amino acid
Overall yielda (%) Time Adduct (h) Stepwise Tandem 11a
24
61
72
11b
22
59
69
11c
20
60
73
11d
20
62
70
11e
22
60
77
11f
22
59
71
Isolated yield.
Preparation of O-propargyl glucosyl aldehyde 1. The O-propargylated diacetonide (3 mmol) was dissolved in a mixture of acetic acid and water (3 : 2, 5 mL) and left at room temperature for 12 h. The reaction mixture was then concentrated by
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evaporation and neutralized with saturated sodium bicarbonate and extracted with dichloromethane (4 × 20 mL) and evaporated to give 3-O-benzyl-1,2-O-isopropylidene-α-D-glucofuranose. The product thus obtained was dissolved in THF (10 mL) and a solution of NaIO4 (1.5 eq.) in water (5 mL) was added. The reaction mixture was vigorously stirred for 5 h and was then filtered. The filtrate was extracted twice with dichloromethane and the combined organic fractions were washed with water and dried over sodium sulfate to O-propargyl glucosyl aldehyde 1 as colorless oil in good yield. Synthesis of O-alkynyl enone fragment 3a. To a solution of O-propargyl glucosyl aldehyde 1 (1 g, 4 mmol) in anhydrous THF (15 mL) and triethyl phosphonoacetate (4 mol), LiOH·H2O (4 mmol) was added and the mixture was stirred for 12 h (monitored by TLC). The solvent evaporated under reduced pressure and the residue was dissolved in dichloromethane (2 × 50 mL) and washed with water (2 × 30 mL). The organic layer was dried (Na2SO4) and evaporated under reduced pressure. The residue was chromatographed over silica gel using hexane–ethyl acetate (4 : 1) as the eluent to yield the desired O-alkynyl enone fragment 3a as a colorless oil in good yield. O-Alkynyl enone 3a. Yield: 92% (1.20 g). Colorless oil. 1H NMR (300 MHz, CDCl3): δ 1.28 (t, J = 7.2 Hz, 3H); 1.33 (s, 3H); 1.51 (s, 3H); 1.64 (d, J = 3 Hz, 1H); 2.48 (t, J = 2.1 Hz, 1H); 4.20 (q, J = 7.2 Hz, 2H); 4.21–4.24 (m, 3H); 4.67–4.68 (m, 1H); 4.83 (s, 1H); 5.97 (d, J = 3.9 Hz, 1H); 6.17 (dd, J = 1.5, 15.6 Hz, 1H); 6.93 (dd, J = 5.4, 15.6 Hz, 1H). 13C NMR (75 MHz, CDCl3): 14.2, 26.1, 26.9, 57.7, 60.4, 75.5, 78.6, 79.2, 82.5, 82.6, 112.0, 123.5, 140.8, 166.0. HRMS (EI) exact mass calc. for C15H20O6H: 297.1338 (M + H) found 297.13302. [α]24.3 +7.6 (c 0.2, CHCl3). D Synthesis of O-alkynyl enone fragment 3b. To a solution of O-propargyl glucosyl aldehyde 1 (1 g, 4 mmol) in anhydrous THF (15 mL) and diethyl 2-(4-bromophenyl)-2-oxoethylphosphonate (4 mmol), LiOH·H2O (4 mmol) was added and the mixture was stirred for 12 h (monitored by TLC). The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane (2 × 50 mL) and washed with water (2 × 30 mL). The organic layer was dried (Na2SO4) and evaporated under reduced pressure and the residue was chromatographed over SiO2 using hexane–ethyl acetate (4 : 1) as the
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eluent to yield the desired O-alkynyl enone fragment 3b as a colorless oil in good yield. O-alkynyl enone 3b. Yield: 88% (1.40 g). Colorless oil. 1H NMR (300 MHz, CDCl3): δ 1.28 (s, 3H); 1.45 (s, 3H); 2.42 (t, J = 2.4 Hz, 1H); 4.12 (d, J = 2.4 Hz, 2H); 4.20 (d, J = 3 Hz, 1H); 4.63 (d, J = 3.6 Hz, 1H); 4.91 (d, J = 3.6 Hz, 1H); 5.94 (d, J = 3.9 Hz, 1H); 6.96 (dd, J = 3.9, 15.3 Hz, 1H); 7.16 (dd, J = 1.8, 15.3 Hz, 1H); 7.35–7.41 (m, 2H); 7.85 (d, J = 8.7 Hz, 2H). 13C NMR (75 MHz, CDCl3): 25.2, 25.8, 56.7, 74.6, 77.6, 78.6, 81.4, 81.5, 103.8, 111.1, 125.2, 127.8, 129.1, 134.7, 138.3, 140.3, 187.6 ppm. HRMS (EI) exact mass calc. for C19H19ClO5H: 363.0999 (M + H) found 363.0990. [α]27.1 +9.61(c 0.2, CHCl3). D Preparation of triazole linkers 8a–d. To a solution of O-alkynyl glucosyl enones 3a–b (3.0 mmol) and N-alkylazides 7a–b (3.2 mmol) in THF (15 mL), H2O (15 mL) was added CuSO4·5 H2O (0.7 mmol) and sodium ascorbate (1.5 mmol). The resulting solution was stirred for 12 h at room temperature. The solvent was evaporated under vacuum and the residue was washed with water and brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using hexane–EtOAc (7 : 3) as the eluent. Triazole linker 8a. Yield: 84% (1.4 g). Orange solid. mp 122–124 °C. IR (KBr): 1718, 1732, 2622 cm−1. 1H NMR (300 MHz, CDCl3): δ 1.18 (t, J = 7.2 Hz, 3H); 1.26 (s, 3H); 1.42 (s, 3H); 1.76–1.80 (m, 1H); 3.67 (t, J = 6 Hz, 1H); 3.81 (d, J = 2.7 Hz, 1H); 4.06–4.13 (m, 2H); 4.18–4.24 (m, 1H); 4.46 (d, J = 12.9 Hz, 1H); 4.54–4.60 (m, 2H); 4.62–4.66 (m, 2H); 5.85 (d, J = 3.6 Hz, 1H); 5.96 (dd, J = 1.2, 15.9 Hz, 1H); 6.32 (dd, J = 4.5, 15.9 Hz, 1H); 6.47 (d, J = 8.1 Hz, 1H); 6.99 (t, J = 7.5 Hz, 1H); 7.37 (t, J = 7.5 Hz, 1H); 7.47 (d, J = 7.2 Hz, 1H); 7.55 (s, 1H). 13C NMR (75 MHz, CDCl3): 12.7, 24.1, 24.7, 25.3, 39.2, 46.7, 59.2, 62.3, 66.5, 77.5, 81.2, 81.5, 103.5, 108.5, 110.6, 116.1, 121.3, 122.5, 124.1, 136.9, 140.1, 148.6, 157.1, 164.9, 180.8 ppm. HRMS (EI) exact mass calc. for C25H28N4O8H: 513.1985 (M + H) found 513.1970. [α]24.9 +7.6 (c 0.2, CHCl3). D Triazole linker 8b. Yield: 86% (1.37 g). Orange solid. mp 132–136 °C. IR (KBr): 1722, 1728, 2632 cm−1. 1H NMR (300 MHz, CDCl3): δ 1.35 (s, 3H); 1.52 (s, 3H); 3.93 (d, J = 3 Hz, 1H); 4.21–4.30 (m, 1H); 4.35–4.43 (m, 1H); 4.55 (d, J = 12.9 Hz, 1H); 4.64 (d, J = 3.9 Hz, 1H); 4.70–4.71 (m, 2H); 4.73–4.76 (m, 2H); 5.98 (d, J = 3.6 Hz, 1H); 6.30 (dd, J = 3.9, 15.3 Hz, 1H); 6.55 (d, J = 8.1 Hz, 1H); 7.03 (t, J = 7.5 Hz, 1H); 7.16 (dd, J = 1.8, 15.6 Hz, 1H); 7.43–7.50 (m, 4H); 7.66 (s, 1H); 7.90 (d, J = 8.7 Hz, 2H). 13C NMR (75 MHz, CDCl3): 23.9, 24.5, 38.4, 45.9, 61.6, 77.1, 80.5, 80.6, 102.7, 107.1, 109.9, 115.3, 121.6, 122.4, 123.0, 123.2, 126.7, 127.9, 133.0, 135.9, 137.5, 139.8, 142.6, 147.9, 156.3, 179.9, 186.4 ppm. HRMS (EI) exact mass calc. for C29H27ClN4O7H: 579.1647 (M + H) found 579.1630. [α]25.9 +3.6 D (c 0.2, CHCl3). Triazole linker 8c. Yield: 82% (1.62 g). Orange solid. mp 144–146 °C. IR (KBr): 1710, 1722, 2636 cm−1. 1H NMR (300 MHz, CDCl3): δ 1.19 (t, J = 7.2 Hz, 3H); 1.24 (s, 3H); 1.41 (s, 3H); 3.99 (d, J = 3 Hz, 1H); 4.10 (q, J = 7.2 Hz, 2H); 4.50–4.63 (m, 3H); 4.67–4.70 (m, 1H); 4.85 (s, 2H); 5.43 (d, J = 1.8 Hz, 2H); 5.86 (d, J = 3.6 Hz, 1H); 6.03 (dd, J = 1.5, 15.9 Hz, 1H); 6.67–6.76 (m, 2H); 7.03 (t, J = 7.5 Hz, 1H); 7.18–7.20 (m, 2H);
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7.26–7.29 (m, 2H); 7.40 (s, 1H); 7.42–7.45 (m, 1H); 7.54 (d, J = 7.2 Hz, 1H). 13C NMR (75 MHz, CDCl3): 14.2, 26.1, 26.7, 43.6, 53.6, 60.4, 64.0, 79.2, 82.7, 83.4, 104.9, 110.8, 112.0, 117.6, 122.8, 123.3, 124.0, 125.5, 128.1, 128.7, 134.6, 135.2, 138.4, 141.2, 144.9, 150.4, 158.2, 166.0, 183.0 ppm. HRMS (EI) exact mass calc. for C31H32N4O8H: 589.2298 (M + H) found 589.2290. [α]25.1 −5.1 (c 0.2, CHCl3). D Triazole linker 8d. Yield: 86% (1.55 g). Orange solid. mp 154–156 °C. IR (KBr): 1714, 1730, 2636 cm−1. 1H NMR (300 MHz, CDCl3): δ 1.27 (s, 3H); 1.44 (s, 3H); 4.08 (d, J = 3 Hz, 1H); 4.52 (d, J = 12.6 Hz, 1H); 4.62 (d, J = 3.6 Hz, 1H); 4.67 (d, J = 12.6 Hz, 1H); 4.82–4.83 (m, 3H); 5.41 (s, 2H); 5.92 (d, J = 3.6 Hz, 1H); 6.65 (d, J = 7.8 Hz, 1H); 6.77 (dd, J = 4.2, 15.3 Hz, 1H); 7.02 (t, J = 7.5 Hz, 1H); 7.10–7.28 (m, 5H); 7.36–7.40 (m, 3H); 7.42 (s, 1H); 7.54 (d, J = 7.5 Hz, 1H); 7.83 (d, J = 8.7 Hz, 2H). 13 C NMR (75 MHz, CDCl3): 26.2, 26.8, 30.9, 43.5, 53.6, 64.0, 79.6, 82.7, 83.3, 104.9, 110.8, 112.2, 117.6, 123.0, 124.0, 125.5, 125.9, 128.1, 128.8, 129.0, 130.1, 134.6, 135.2, 135.6, 138.3, 139.6, 141.8, 144.7, 150.4, 158.2, 183.0, 188.5 ppm. HRMS (EI) exact mass calc. for C35H31ClN4O7H: 655.1960 (M + H) found 655.1966. [α]27.9 −4.6 (c 0.2, CHCl3). D General procedure for the synthesis of macrocycles 10a–f and 11a–f Method A: two step sequential double [3 + 2]cycloaddition reaction. A solution of triazoles 8a–d (0.5 mmol) and L-proline 9a/thiaproline 9b/sarcosine 9c (0.5 mmol) was refluxed in dry toluene (50 mL) under a N2 atmosphere for 8–12 h at 110 °C using the Dean–Stark apparatus. After the completion of reaction as indicated by TLC, toluene was evaporated under reduced pressure. The crude product was washed with water and extracted with ethylacetate (4 × 20 mL). The combined organic layers were dried (MgSO4) and filtered, concentrated in a vacuum. The crude product was purified by column chromatography (hexane–EtOAc, 3 : 7) to give the macrocycles in moderate yield. Method B: one-pot sequential tandem double [3 + 2]cycloaddition reaction. To the O-alkynyl glucosyl enones 3a–b (300 mg, 1 mmol) in dry acetonitrile (10 ml) in N2 atm were added N-alkylazides 7a–b (220 mg, 1 mmol) and secondary amino acid (1 equiv.) followed by diisopropylethylamine (DIPEA) (2.5 equiv.) and CuI (3.0 equiv.).The reaction mixture was stirred for 10–12 h at room temperature. After completion of the reaction as evidenced from TLC, the reaction mixture was refluxed for 12 h. The solvent was evaporated under vacuum and the residue was washed with water and brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using a hexane–EtOAc (3 : 7) mixture as the eluent to give the macrocycles in good yield. Macrocycle 10a. Yield: 76% (0.25 g). White crystalline solid. mp 176–178 °C. IR (KBr): 1381, 1612, 1720, 2644 cm−1. 1H NMR (400 MHz, CDCl3): δ 0.90 (t, J = 7.2 Hz, 3H); 1.32 (s, 3H); 1.48 (s, 3H); 1.73–1.81 (m, 2H); 1.83–1.94 (m, 1H); 1.98–2.05 (m, 1H); 2.10–2.15 (m, 1H); 2.81 (t, J = 6.8 Hz, 1H); 2.95–2.99 (m, 1H); 3.15–3.22 (m, 1H); 3.62–3.70 (m, 2H); 3.87 (d,
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J = 7.2 Hz, 1H); 3.90–3.98 (m, 2H); 4.13–4.18 (m, 1H); 4.30–4.37 (m, 1H); 4.50–4.58 (m, 1H); 4.62 (d, J = 4.0 Hz, 1H); 4.64 (d, J = 12.0 Hz, 1H); 4.73 (d, J = 13.6 Hz, 1H); 4.92 (dd, J = 1.6, 14.0 Hz, 1H); 5.86 (d, J = 4.0 Hz, 1H); 6.88 (d, J = 8.0 Hz, 1H); 7.05 (t, J = 7.6 Hz, 1H); 7.29 (d, J = 7.6 Hz, 1H); 7.35–7.39 (m, 1H); 7.60 (s, 1H); 13C NMR (75 MHz, CDCl3): 13.8, 24.9, 26.2, 26.6, 28.5, 39.5, 46.7, 47.4, 48.6, 55.8, 60.7, 61.2, 71.2, 72.3, 76.6, 79.2, 80.1, 82.0, 103.8, 107.4, 111.6, 122.7, 126.0, 126.1, 126.8, 129.7, 141.7, 173.3, 178.2 ppm. HRMS (EI) exact mass calc. for C29H35N5O7H: 566.2615 (M + H) found 566.2611. [α]26.6 −9.43 D (c 0.2, CHCl3). Macrocycle 10b. Yield: 72% (0.23 g). White crystalline solid. mp 183–186 °C. IR (KBr): 1055, 1378, 1622, 1718, 2634 cm−1. 1 H NMR (500 MHz, CDCl3): δ 1.26 (s, 3H); 1.44 (s, 3H); 1.71–1.80 (m, 2H); 1.84–1.90 (m, 1H); 1.99–2.02 (m, 1H); 2.10–2.13 (m, 1H); 2.68 (t, J = 7.5 Hz, 1H); 3.26–3.30 (m, 2H); 4.04 (t, J = 2.5 Hz, 1H); 4.30 (d, J = 2.0 Hz, 1H); 4.33–4.37 (m, 1H); 4.41–4.44 (m, 2H); 4.51 (d, J = 12.5 Hz, 1H); 4.62 (d, J = 4 Hz, 1H); 4.72–4.75 (m, 1H); 4.91 (d, J = 12.5 Hz, 1H); 4.96 (d, J = 7.0 Hz, 1H); 5.69 (d, J = 4.0 Hz, 1H); 6.57 (d, J = 8.0 Hz, 1H); 6.74 (t, J = 7.5 Hz, 1H); 7.04 (t, J = 7.5 Hz, 1H); 7.08 (d, J = 7.5 Hz, 1H); 7.16–7.19 (m, 2H); 7.21–7.23 (m, 2H); 7.62 (s, 1H). 13 C NMR (75 MHz, CDCl3): 13.1, 25.1, 25.5, 28.0, 39.1, 46.8, 47.1, 49.1, 53.0, 59.4, 61.1, 67.4, 71.2, 76.2, 77.1, 80.3, 81.6, 102.3, 106.2, 110.5, 121.6, 123.6, 124.1, 127.4, 127.6, 128.4, 136.2, 137.6, 141.3, 143.8, 177.0, 200.9 ppm. HRMS (EI) exact mass calc. for C33H34ClN5O6H: 632.2275 (M + H) found 632.2274. [α]28.4 −4.2 (c 0.2, CHCl3). D Macrocycle 10c. Yield: 70% (0.24 g). White crystalline solid. mp 196–198 °C. IR (KBr): 1050, 1388, 1632, 1724, 2638 cm−1. 1 H NMR (300 MHz, CDCl3): δ 0.84 (t, J = 7.2 Hz, 3H); 1.27 (s, 3H); 1.45 (s, 3H); 2.81 (d, J = 6.6 Hz, 1H); 3.03–3.08 (m, 1H); 3.19 (t, J = 9.9 Hz, 1H); 3.32–3.42 (m, 2H); 3.54 (d, J = 9.3 Hz, 1H); 3.68 (d, J = 14.4 Hz, 1H); 3.73–3.79 (m, 1H); 3.82–3.88 (m, 2H); 3.98 (d, J = 9.3 Hz, 1H); 4.32–4.36 (m, 1H); 4.41–4.45 (m, 1H); 4.51–4.61 (m, 1H); 4.61–4.73 (m, 3H); 4.89 (d, J = 13.8 Hz, 1H); 5.87 (d, J = 3.9 Hz, 1H); 6.80 (d, J = 7.8 Hz, 1H); 7.02 (t, J = 7.5 Hz, 1H); 7.31 (d, J = 7.8 Hz, 1H); 7.36 (d, J = 7.2 Hz, 1H); 7.89 (s, 1H). 13C NMR (75 MHz, CDCl3): 12.7, 25.2, 26.0, 34.0, 42.5, 46.7, 51.6, 55.3, 60.2, 60.3, 72.4, 77.4, 78.0, 81.8, 82.9, 103.6, 106.3, 110.6, 122.1, 123.9, 125.0, 129.1, 140.6, 141.5, 170.1, 178.4 ppm. HRMS (EI) exact mass calc. for C28H33N5O7SH: 584.2179 (M + H) found 584.2171. [α]25.5 −6.18 D (c 0.2, CHCl3). Macrocycle 10d. Yield: 76% (0.25 g). White crystalline solid. mp 148–151 °C. IR (KBr): 1055, 1373, 1628, 1730, 2632 cm−1. 1 H NMR (500 MHz, CDCl3): δ 1.26 (s, 3H); 1.44 (s, 3H); 2.93–2.96 (m, 2H); 3.03–3.33 (m, 1H); 3.39–3.40 (m, 1H); 3.54–3.58 (m, 2H); 4.13 (t, J = 2.5 Hz, 1H); 4.25 (d, J = 2.5 Hz, 1H); 4.43–4.47 (m, 2H); 4.54 (d, J = 12.5 Hz, 1H); 4.63–4.64 (m, 2H); 4.76–4.78 (m, 1H); 4.89 (d, J = 12.5 Hz, 1H); 4.98 (d, J = 5.0 Hz, 1H); 5.71 (d, J = 4.0 Hz, 1H); 6.60 (d, J = 7.5 Hz, 1H); 6.77 (t, J = 7.5 Hz, 1H); 6.98 (d, J = 7.0 Hz, 1H); 7.05–7.08 (m, 1H); 7.17–7.21 (m, 4H); 7.66 (s, 1H). 13C NMR (75 MHz, CDCl3): 25.1, 25.6, 31.4, 38.7, 42.3, 44.4, 47.1, 56.3, 61.0, 67.4, 70.7, 78.3, 80.6, 81.3, 102.4, 106.3, 110.6, 122.1, 122.9, 124.0, 126.3,
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127.4, 128.3, 128.8, 135.8, 137.5, 140.9, 143.5, 176.9, 198.0 ppm. HRMS (EI) exact mass calc. for C32H32ClN5O6SNa: 672.1660 (M+) found 672.1661. [α]25.8 −5.04 (c 0.2, CHCl3). D Macrocycle 10e. Yield: 74% (0.23 g). White crystalline solid. mp 144–146 °C. IR (KBr): 1044, 1380, 1622, 1731, 2632 cm−1. 1 H NMR (400 MHz, CDCl3): δ 0.93 (t, J = 7.2 Hz, 3H); 1.32 (s, 3H); 1.49 (s, 3H); 2.08 (s, 3H); 3.21–3.25 (m, 1H); 3.27 (t, J = 7.2 Hz, 1H); 3.57 (t, J = 7.2 Hz, 1H); 3.62–3.70 (m, 3H); 3.87–3.95 (m, 1H); 3.97 (d, J = 3.2 Hz, 1H); 4.15 (t, J = 3.2 Hz, 1H); 4.34–4.41 (m, 1H); 4.54–4.61 (m, 1H); 4.64–4.65 (m, 1H); 4.66 (d, J = 13.2 Hz, 1H); 4.75 (d, J = 13.2 Hz, 1H); 4.92 (dd, J = 1.2, 14.0 Hz, 1H); 5.87 (d, J = 4.0 Hz, 1H); 6.86, (d, J = 8.0 Hz, 1H); 7.05–7.09 (m, 1H); 7.14–7.16 (m, 1H); 7.32–7.36 (m, 1H); 7.70 (s, 1H). 13C NMR (75 MHz, CDCl3): 12.8, 25.1, 25.6, 34.3, 38.1, 38.3, 46.4, 53.6, 59.5, 59.7, 60.2, 72.1, 78.3, 80.5, 81.2, 102.9, 106.1, 110.5, 122.1, 124.4, 125.2, 125.6, 128.5, 140.4, 141.9, 170.9, 177.8 ppm. HRMS (EI) exact mass calc. for C27H33N5O7H: 540.2458 (M + H) found 540.2455. [α]26.3 −7.84 D (c 0.2, CHCl3). Macrocycle 10f. Yield: 71% (0.22 g). White crystalline solid. mp 155–157 °C. IR (KBr): 1048, 1376, 1632, 1731, 2624 cm−1. 1 H NMR (500 MHz, CDCl3): δ 1.26 (s, 3H); 1.44 (s, 3H); 2.01 (s, 3H); 3.37–3.47 (m, 2H); 3.52–3.59 (m, 1H); 3.61–3.63 (m, 1H); 4.10 (t, J = 2.5 Hz, 1H); 4.16 (d, J = 3.0 Hz, 1H); 4.46–4.48 (m, 2H); 4.53–4.54 (m, 1H); 4.58 (d, J = 13.0 Hz, 1H); 4.60 (d, J = 4.0 H, 1H); 4.79–4.81 (m, 1H); 4.84 (d, J = 13.0 Hz, 1H); 5.71 (d, J = 4.0 Hz, 1H); 6.66 (d, J = 7.5 Hz, 1H); 6.78 (t, J = 7.5 Hz, 1H); 6.92–6.93 (m, 1H); 7.09–7.12 (m, 1H); 7.19–7.24 (m, 2H); 7.48 (d, J = 8.5 Hz, 2H); 7.63 (s, 1H). 13C NMR (75 MHz, CDCl3): 24.3, 24.8, 33.1, 37.5, 38.4, 45.8, 52.0, 57.8, 59.5, 71.9, 79.1, 79.6, 80.2, 101.5, 105.5, 109.7, 121.5, 123.0, 123.4, 125.2, 126.7, 127.8, 128.2, 134.9, 136.9, 140.0, 142.3, 176.4, 198.7 ppm. HRMS (EI) exact mass calc. for C31H32ClN5O6H: 606.2119 (M + H) found 606.2112. [α]25.4 −6.59 (c 0.2, CHCl3). D Macrocycle 11a. Yield: 72% (0.23 g). White crystalline solid. mp 166–168 °C. IR (KBr): 1038, 1389, 1632, 1718, 2639 cm−1. 1 H NMR (500 MHz, CDCl3): δ 0.73 (t, J = 7.5 Hz, 3H); 1.24 (s, 3H); 1.47 (s, 3H); 1.63 (d, J = 6.5 Hz, 1H); 1.69–1.77 (m, 1H); 1.79–1.87 (m, 2H); 2.16–2.21(m, 1H); 2.58–2.63 (m, 1H); 2.68–2.71 (m, 1H); 3.12–3.16 (m, 2H); 3.54–3.62 (m, 2H); 4.16–4.17 (m, 1H); 4.24–4.27 (m, 1H); 4.44 (d, J = 14.0 Hz, 1H); 4.56 (d, J = 14.0 Hz, 1H); 4.62–4.66 (m, 2H); 4.84 (d, J = 14.0 Hz, 1H); 5.07 (d, J = 14.0 Hz, 1H); 5.71 (d, J = 14.0 Hz, 1H); 5.78 (d, J = 4.0 Hz, 1H); 6.89 (s, 1H); 6.92 (t, J = 7.5 Hz, 1H); 7.07 (d, J = 8.0 Hz, 1H); 7.11 (d, J = 7.5 Hz, 1H); 7.15 (d, J = 7.5 Hz, 1H); 7.20–7.26 (m, 2H); 7.33 (t, J = 8.0 Hz, 1H); 7.56 (d, J = 8.0 Hz, 1H). 13C NMR (75 MHz, CDCl3): 12.8, 25.0, 25.5, 26.1, 29.4, 42.8, 47.3, 47.8, 53.4, 57.9, 59.4, 59.9, 71.1, 71.5, 78.2, 79.5, 83.4, 103.5, 107.9, 110.7, 121.0, 122.4, 125.3, 125.8, 126.6, 127.7, 128.4, 128.6, 131.0, 134.0, 135.9, 141.7, 142.0, 171.5, 177.1 ppm. HRMS (EI) exact mass calc. for C35H39N5O7H: 642.2928 (M + H) found 642.2926. [α]28.8 −8.74 (c 0.2, CHCl3). D Macrocycle 11b. Yield: 69% (0.22 g). White crystalline solid. mp 170–172 °C. IR (KBr): 1050, 1398, 1623, 1716, 2663 cm−1. 1 H NMR (300 MHz, CDCl3): δ 1.27 (s, 3H); 1.47 (s, 3H); 2.20–2.34 (m, 2H); 2.59–2.64 (m, 1H); 2.75–2.76 (m, 1H);
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2.80–2.85 (m, 1H); 3.17 (d, J = 4.5 Hz, 1H); 3.26–3.30 (m, 1H); 3.98–4.03 (m, 2H); 4.33–4.35 (m, 1H); 4.42–4.49 (m, 2H); 4.54 (d, J = 14.1 Hz, 1H); 4.65 (d, J = 3.9 Hz, 1H); 4.90 (d, J = 14.1 Hz, 1H); 5.14 (d, J = 14.1 Hz, 1H); 5.65 (d, J = 14.1 Hz, 1H); 5.75 (d, J = 3.9 Hz, 1H); 5.91 (s, 1H); 6.50–6.56 (m, 3H); 6.87 (d, J = 7.5 Hz, 1H); 6.98–7.00 (m, 4H); 7.07–7.12 (m, 2H); 7.29–7.38 (m, 2H); 7.73 (d, J = 7.8 Hz, 1H). 13C NMR (75 MHz, CDCl3): 25.9, 26.2, 28.6, 30.8, 42.8, 47.5, 49.4, 53.2, 57.3, 59.7, 70.0, 71.8, 79.2, 80.7, 82.1, 103.1, 107.0, 111.1, 121.2, 122.2, 124.1, 126.4, 127.1, 127.6, 127.9, 128.3, 131.7, 135.4, 136.5, 142.4, 176.7, 198.4 ppm. HRMS (EI) exact mass calc. for C39H38ClN5O6H: 708.2589 (M + H) found 708.2584. [α]26.4 −6.6 D (c 0.2, CHCl3). Macrocycle 11c. Yield: 73% (0.24 g). White crystalline solid. mp 182–184 °C. IR (KBr): 1034, 1367, 1633, 1738, 2665 cm−1. 1 H NMR (500 MHz, CDCl3): δ 0.74 (t, J = 7.0 Hz, 3H); 1.26 (s, 3H); 1.46 (s, 3H); 1.78 (d, J = 2.1 Hz, 1H); 2.08–2.86 (m, 2H); 3.05–3.09 (m, 1H); 3.31–3.32 (m, 1H); 3.32 (d, J = 8.5 Hz, 1H); 3.48–3.55 (m, 2H); 3.38 (d, J = 8.5 Hz, 1H); 3.96–4.00 (m, 1H); 4.48 (d, J = 4.0 Hz, 1H); 4.50–4.53 (m, 1H); 4.61 (d, J = 9.5 Hz, 1H); 4.64 (d, J = 9.5 Hz, 1H); 4.71 (d, J = 4.0 Hz, 1H); 4.72–4.75 (m, 1H); 5.12 (d, J = 13.5 Hz, 1H); 5.67 (d, J = 13.5 Hz, 1H); 5.81 (d, J = 4.0 Hz, 1H); 6.92 (s, 1H); 6.95 (t, J = 7.5 Hz, 1H); 7.08 (d, J = 7.5 Hz, 1H); 7.11 (d, J = 7.5 Hz, 1H); 7.16–7.20 (m, 2H); 7.22–7.23 (m, 1H); 7.30–7.34 (m, 1H); 7.58–7.59 (m, 1H). 13C NMR (75 MHz, CDCl3): 12.8, 25.5, 26.0, 34.8, 42.0, 43.3, 50.1, 53.6, 57.2, 59.5, 59.8, 71.3, 73.6, 76.5, 79.0, 81.7, 103.6, 107.3, 110.8, 121.3, 121.5, 123.4, 125.7, 126.6, 127.4, 128.5, 129.0, 131.5, 133.9, 135.6, 142.0, 142.1, 169.5, 177.0 ppm. HRMS (EI) exact mass calc. for C34H37N5O7SH: 660.2492 (M + H) found 660.2490. [α]25.4 −4.38 (c 0.2, CHCl3). D Macrocycle 11d. Yield: 70% (0.23 g). White crystalline solid. mp 202–204 °C. IR (KBr): 1048, 1387, 1622, 1738, 2676 cm−1. 1 H NMR (300 MHz, CDCl3): δ 1.27 (s, 3H); 1.48 (s, 3H); 2.77–2.78 (m, 1H); 2.84–2.91 (m, 1H); 2.96 (d, J = 9.0 Hz, 1H); 3.03–3.08 (m, 1H); 3.20 (d, J = 4.8 Hz, 1H); 3.46 (s, 2H); 4.13 (d, J = 13.8 Hz, 1H); 4.23–4.30 (m, 1H); 4.45–4.55 (m, 3H); 4.67 (d, J = 3.9 Hz, 1H); 4.89 (d, J = 13.8 Hz, 1H); 5.18 (d, J = 14.1 Hz, 1H); 5.70 (d, J = 14.1 Hz, 1H); 5.73 (d, J = 3.9 Hz, 1H); 6.35 (s, 1H); 6.59 (t, J = 7.5 Hz, 1H); 6.80 (d, J = 7.2 Hz, 3H); 6.94 (d, J = 7.8 Hz, 1H); 7.02–7.09 (m, 4H); 7.26 (d, J = 7.8 Hz, 1H); 7.40 (d, J = 7.2 Hz, 1H); 7.69 (d, J = 8.1 Hz, 1H). 13C NMR (75 MHz, CDCl3): 25.8, 26.2, 32.6, 41.6, 43.0, 45.0, 53.3, 59.4, 68.5, 71.8, 76.2, 78.2, 80.1, 81.5, 103.3, 107.1, 111.1, 121.7, 122.5, 122.8, 125.6, 126.6, 127.2, 127.5, 127.8, 128.3, 128.7, 131.5, 134.6, 135.5, 136.1, 137.6, 141.2, 142.1, 176.7, 195.3 ppm. HRMS (EI) exact mass calc. for C38H36ClN5O6SH: 726.2153 (M + H) found 726.2153. [α]28.7 −9.2 (c 0.2, CHCl3). D Macrocycle 11e. Yield: 77% (0.24 g). White crystalline solid. mp 192–196 °C. IR (KBr): 1032, 1376, 1632, 1721, 2654 cm−1. 1 H NMR (300 MHz, CDCl3): δ 0.79 (t, J = 7.2 Hz, 3H); 1.24 (s, 3H); 1.41 (s, 3H); 1.48 (d, J = 5.1 Hz, 1H); 2.06 (s, 3H); 2.98–3.06 (m, 1H); 3.14 (d, J = 4.8 Hz, 1H); 3.29 (t, J = 8.4 Hz, 1H); 3.46 (t, J = 8.4 Hz, 1H); 3.56–3.68 (m, 2H); 4.25–4.30 (m, 1H); 4.44–4.54 (m, 2H); 4.62–4.67 (m, 2H); 4.87 (d, J = 14.4 Hz, 1H); 5.06 (d, J = 14.1 Hz, 1H); 5.73–5.79 (m, 2H); 6.92–7.11
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(m, 5H); 7.21–7.33 (m, 3H), 7.51 (d, J = 7.8 Hz, 1H). 13C NMR (75 MHz, CDCl3): 12.9, 25.6, 26.1, 34.5, 38.6, 42.8, 53.4, 55.1, 58.9, 59.5, 59.8, 73.2, 77.5, 79.4, 83.3, 103.6, 107.8, 110.8, 121.7, 122.5, 124.2, 125.7, 126.6, 127.6, 128.4, 128.6, 130.7, 134.4, 135.9, 141.5, 142.1, 170.1, 177.5 ppm. HRMS (EI) exact mass calc. for C33H37N5O7H: 616.2771 (M + H) found 616.2772. [α]25.8 −5.04 (c 0.2, CHCl3). D Macrocycle 11f. Yield: 71% (0.22 g). White crystalline solid. mp 188–190 °C. IR (KBr): 1040, 1392, 1633, 1740, 2677 cm−1. 1 H NMR (300 MHz, CDCl3): δ 1.26 (s, 3H); 1.47 (s, 3H); 2.12 (s, 3H); 3.01–3.10 (m, 2H); 3.45 (t, J = 8.7 Hz, 1H); 3.59 (t, J = 8.7 Hz, 1H); 4.06–4.10 (m, 1H); 4.46–4.51 (m, 4H); 4.65 (d, J = 3.3 Hz, 1H); 4.99 (d, J = 14.1 Hz, 1H); 5.10 (d, J = 14.1 Hz, 1H); 5.75–5.78 (m, 2H); 6.52–6.57 (m, 1H); 6.62–6.64 (m, 2H); 6.91 (d, J = 8.1 Hz, 1H); 6.99–7.01 (m, 2H); 7.01–7.08 (m, 3H); 7.38–7.45 (m, 3H); 7.66–7.67 (m, 1H). 13C NMR (75 MHz, CDCl3): 25.9, 26.2, 34.5, 38.4, 42.5, 53.2, 57.9, 59.2, 73.7, 76.2, 77.8, 79.7, 82.7, 103.4, 107.2, 111.0, 121.7, 122.6, 124.2, 124.9, 126.4, 127.2, 127.4, 127.6, 128.3, 131.0, 134.7, 135.9, 136.3, 137.5, 141.2, 142.2, 177.3, 196.2 ppm. HRMS (EI) exact mass calc. for C37H36ClN5O6H: 682.2432 (M + H) found 682.2310. [α]28.4 −4.2 (c 0.2, CHCl3). D
Acknowledgements The authors RP, SP and RR thank DST-FIST program for the NMR facility. The authors wish to thank Ms V. Sabari for single crystal X-ray data. RP thanks CSIR New Delhi for the award of SRF. RR thanks UGC, New Delhi for BSR faculty fellowship.
Notes and references 1 (a) A. T. Londregan, K. A. Farley, C. Limberakis, P. B. Mullins and D. W. Piotrowski, Org. Lett., 2012, 14, 2890; (b) S. Lee, C.-H. Chen and A. H. Flood, Nat. Chem., 2013, 5, 704. 2 (a) B. Beck, G. Larbig, B. Mejat, M. Magnin-Lachaux, A. Picard, E. Herdtweck and A. Do1mling, Org. Lett., 2003, 5, 1047; (b) P. Janvier, M. Bois-Choussy, H. Bienaym and J. Zhu, Angew. Chem., Int. Ed., 2003, 42, 811; (c) F. Erver and G. Hilt, Org. Lett., 2012, 14, 1884. 3 (a) M. Pascu, A. Ruggi, R. Scopelliti and K. Severin, Chem. Commun., 2013, 49, 45; (b) T.-F. Niu, M. Sun, M.-F. Lv, W.-B. Yi and C. Cai, Org. Biomol. Chem., 2013, 11, 7232; (c) T. Pirali, G. C. Tron and J. Zhu, Org. Lett., 2006, 8, 4145; (d) H. H. Nguyen, T. A. Palazzo and M. J. Kurth, Org. Lett., 2013, 15, 4492. 4 (a) C. E. P. Galvis and V. V. Kouznetsov, Org. Biomol. Chem., 2013, 11, 7372; (b) N. Lashgari and G. M. Ziarani, ARKIVOC, 2012, 277; (c) N. Arumugam, G. Periyasami, R. Raghunathan, S. Kamalraj and J. Muthumary, Eur. J. Med. Chem., 2011, 46, 600; (d) I. Coldham and R. Hufton, Chem. Rev., 2005, 105, 2765; (e) G. Pandey, P. Banerjee and S. R. Gadre, Chem.
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Rev., 2006, 106, 4484; (f ) A. R. Suresh Babu, D. Gavaskar and R. Raghunathan, Tetrahedron Lett., 2012, 53, 6676; (g) D. Gavaskar, R. Raghunathan and A. R. Suresh Babu, Tetrahedron Lett., 2014, 55, 2217. (a) J. W. Lee, S. Samal, N. Selvapalam, H.-J. Kim and K. Kim, Acc. Chem. Res., 2003, 36, 621; (b) D. Ma, G. Hettiarachchi, D. Nguyen, B. Zhang, J. B. Wittenberg, P. Y. Zavalij, V. Briken and L. Isaacs, Nat. Chem., 2012, 4, 503. T. W. Bell and N. M. Hext, Chem. Soc. Rev., 2004, 33, 589. A. P. D. Silva, H. Q. N. Gunaratne, T. Gunnlaugsson, A. J. M. Huxley, C. P. McCoy, J. T. Rademacher and T. E. Rice, Chem. Rev., 1997, 97, 1515. (a) N. Halland, H. Blum, C. Buning, M. Kohlmann and A. Lindenschmidt, ACS Med. Chem. Lett., 2014, 5, 193; (b) E. A. Jefferson, S. Arakawa, L. B. Blyn, A. Miyaji, S. A. Osgood, R. Ranken, L. M. Risen and E. E. Swayze, J. Med. Chem., 2002, 45, 3430. E. Marsault and M. L. Peterson, J. Med. Chem., 2011, 54, 1961. (a) M. Pintal, B. Kryczka, A. Marsura and S. Porwanski, Carbohydr. Res., 2014, 386, 18; (b) S. I. Moreno-Olivares, R. Cervantes and J. Tiburcio, J. Org. Chem., 2013, 78, 10724. (a) L.-S. Feng, M.-L. Liu, B. Wang, Y. Chai, X.-Q. Hao, S. Meng and H.-Y. Guo, Eur. J. Med. Chem., 2010, 45, 3407; (b) A. Cane, M. C. Tournaire, D. Barritault and M. CrumeyrolleArias, Biochem. Biophys. Res. Commun., 2000, 276, 379. (a) E. M. Driggers, S. P. Hale, J. Lee and N. K. Terrett, Nat. Rev. Drug Discovery, 2008, 7, 608; (b) M. S. Butler, Nat. Prod. Rep., 2005, 22, 162.
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Cite this: DOI: 10.1039/c4ob01778a
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Rapid assembly of heterocycle grafted macrocycles via tandem one-pot double 1,3-dipolar cycloaddition reaction†
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R. Prasanna, S. Purushothaman and R. Raghunathan* Synthesis of triazole linked macrocycles grafted with glycospiroheterocycle was accomplished by stereoand regioselective tandem double 1,3-dipolar cycloaddition (1,3-DC) reaction. By this method we could Received 20th August 2014, Accepted 24th September 2014
construct complex chiral macrocycles in good yields from the easily available starting materials and we could achieve the synthesis of two heterocyclic rings involving simultaneous formation of five bonds in
DOI: 10.1039/c4ob01778a
one-pot reaction. The structures of the macrocycles were confirmed by spectroscopic methods and
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single crystal XRD.
Introduction The important objective in modern organic synthesis is to develop new methods for the construction of complex molecules with high synthetic efficiency.1 Multicomponent reactions (MCRs) are essentially atom economical processes in which complex heterocycles are synthesized from easily available starting materials in a facile one-pot reaction.2,3 Within this class, multicomponent 1,3-DC reaction has been widely used for the construction of biologically significant spiro-oxindole heterocyclic systems.4 Macrocycles are found to have diverse applications in supramolecular chemistry as sensors, phase-transfer catalysts, molecular pores and in drug delivery.5,6 In addition, the conformationally rigid cyclic backbone makes the macrocycles highly selective for ion recognition.7 Numerous macrocyclic compounds with biological significance are reported in the literature.8,9 A progressive interest has been directed to the chemistry of the crown ethers containing macrocycles, since, these macrocycles are found to exhibit interesting host–guest complexation.10 Isatin and its derivatives are known to be privileged scaffolds with a broad spectrum of biological properties such as anti-HIV, anti-TB activity, anticancer, antifungal and antimycobacterial, hence isatin analogs have fascinated both medicinal and synthetic chemist’s interest.11Sugar incorporated natural products forms part of important bioactive macro-
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai-600025, Tamil Nadu, India. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental details and copies of NMR spectra for all new compounds. CCDC 888096 and 888097. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ob01778a
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cycles such as erythromycin, rapamycin, vancomycin, and epothilone.12 Encouraged by the above results, we were prompted to construct hybrid glyco-conjugated isatin derived macrocycles. However, the availability of a short and efficient method for the synthesis of such macrocycles still remains a challenge.13 In our continued efforts for the construction of such molecules by efficient synthetic methods14,15 we propose to use a one-pot tandem double 1,3-dipolar cycloaddition reaction for the synthesis of heterocycle grafted sugar macrocycles. There are no previous reports in the literature on one-pot tandem double 1,3-DC reaction (“click reaction” followed by cycloaddition of azomethine ylide (AMY)).
Results and discussion We have accomplished the synthesis of glucosylspiro-pyrrolizidine grafted macrocycle 10a with a triazole linker by a one-pot double 1,3-DC reaction. The starting materials for the multicomponent reaction O-propargyl glucosyl-enone ester 3a (alkyne fragment) and N-alkyl/benzyl azido isatin 7a (azide fragment) were prepared from D-glucose and isatin respectively (Scheme 1). Synthesis of alkyne fragments 3a–b was achieved from 16 D-glucose by adopting a reported procedure (Scheme 2). The azide fragment was synthesized from isatin as shown in Scheme 3.17 Isatin 4 was reacted with 1,2-dibromoethane/ α,α′-dibromo-p-xylene 5a/5b to give N-alkyl/benzyl bromo isatin 6a/6b. The bromo compound was then converted into azide 7a/7b by treating with NaN3 in DMSO. The structure of N-alkyl/ benzyl azido isatins 7a–b was confirmed by 1H and 13C NMR spectra. Before carrying out the tandem one-pot protocol, we studied the feasibility of obtaining the macrocycles using a
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Scheme 1
Synthetic plan.
Scheme 2
Synthesis of alkyne fragments 3a–b.
Scheme 3
Synthesis of azide fragments 7a–b.
Scheme 4
Model reaction: synthesis of triazole linker 8a.
two step approach. In the first step, the O-alkynyl enone 3a and N-alkyl/benzyl azido isatin 7a were subjected to click reaction with CuSO4·5H2O and sodium ascorbate in THF–water to give 1,4-triazole 8a in good yield (Scheme 4). The structure of the compound 8a was characterized by spectroscopic methods. A neat singlet at δ 7.55 corresponding to triazole –CH– proton proved the presence of a triazole unit. In the 13C NMR spectrum of 8a the carbonyl carbons exhibited peaks at 157.1, 164.9 and 180.8 ppm. Having synthesized the N-isatinyl triazole linked glucosyl ester 8a in good yield; an intramolecular azomethine ylide
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cycloaddition reaction was performed for the synthesis of glucosylspiro-oxindolopyrrolizidine macrocycle 10a. Thus, the reaction of equimolar amounts of compound 8a and L-proline 9a in refluxing acetonitrile gave the macrocycle 10a, but the product was obtained in low yield. The yield of the product could be improved (72%) using toluene as a solvent under reflux conditions in the Dean–Stark apparatus (Scheme 5, Table 1). After confirming the formation of a macrocycle by a stepwise methodology, the tandem one-pot double 1,3-DC reaction was carried out by reacting O-propargyl enone 3a, N-alkyl azido
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Scheme 5
Table 1
Paper
Model reaction: synthesis of macrocycle 10a.
Effect of solvent on the yield of reaction
No.
Solvent
Temperature (°C)
Time (h)
Yielda (%)
1 2 3 4 5 6
Toluene Benzene CH3CN CH3OH DMF DMSO
Reflux Reflux Reflux Reflux 120 120
6 6 12 24 3 3
72 45 65 32 — —
a
Isolated yield.
isatin 7a and secondary amino acid L-proline 9a in a one-pot reaction. The reactants were subjected to ‘click’ reaction with CuI, N,N-diisopropylethylamine (DIEA) in dry CH3CN at room temperature to give the 1,4-triazoles 8a–b. TLC analysis clearly showed the completion of click reaction and the formation of a single product. The reaction mixture was then heated to reflux without isolation of 1,4-triazole. The azomethine ylide generated by secondary amino acid 9a with an N-isatinyl diketone unit reacted intramolecularly with glucosyl ester 8a to give triazole linked glucosyl spiro-oxindole pyrrolizidine macrocycle 10a in a one-pot three component reaction. This tandem methodology offers simultaneous formation of two heterocyclic rings with the formation of five bonds and a complex glucosylmacrocycle in good yields (72–76%) (Scheme 6). The methodology was extended for the synthesis of a variety of macrocycles using the enone 3b and dipoles generated from other amino acids and active ketones. The results are summarized in Table 2. Since the tandem methodo-
Scheme 6
logy required only one stage of purification, the yield of the product in the reaction is better than in a stepwise reaction. The structure and the regiochemistry of the cycloadducts 10a–f were established by spectroscopic data. In the IR spectrum of 10a, the two carbonyl groups showed peaks at 1720 and 1612 cm−1. The Ha proton resonated as a doublet at δ 3.87 (d, J = 7.2 Hz). A multiplet in the region of δ 2.95–2.99 was observed for the Hb proton. This clearly proved the regio- and stereoselectivity of the cycloaddition reaction. The presence of N-methine carbon of pyrrolizidine was confirmed by the signal at 71.2 ppm in the 13C NMR spectrum of 10a. The spiro carbon and ester carbonyl carbon exhibited peaks at 72.3 and 173.3 ppm respectively. Moreover, the cycloadduct 10a exhibited a peak at m/z 566.2611 (M+ + 1) in HRMS. Similarly, the 1H and 13C spectra for 10b–f showed signals at the expected δ values. Finally, the regio- and stereochemical outcome of the cycloaddition reaction was confirmed by a single crystal X-ray analysis of the cycloadduct 10e (Fig. 1).18 With a view to explore the potential application of the tandem methodology, similar types of reactions were carried out with the p-xylyl group as a spacer unit. Thus, the reaction between N-benzyl azido isatin 7b, O-propargyl enones 3a–b and secondary amino acids (L-proline 9a, thiazolidine-4carboxylic acid 9b and sarcosine 9c) yielded glycosyl-spiroheterocycle grafted macrocycles 11a–f in good yields (Scheme 7). The results are summarized in Table 3. The structure and the regiochemistry of all the cycloadducts 11a–f were established by spectroscopic data. The 1H and 13 C spectra for 11a–f showed signals at the expected δ values.
Tandem one-pot 1,3-DC reaction.
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Organic & Biomolecular Chemistry Tandem reaction of N-alkyl azido isatin 7a
Conclusions a
O-Alkynyl enone
Amino acid
Overall yield (%) Time Adduct (h) Stepwise Tandem 10a
24
63
76
10b
22
61
72
In conclusion, we have developed a simple and an efficient protocol for the synthesis of triazole linked glucosylspiroheterocycle grafted macrocycles through a tandem double 1,3dipolar cycloaddition methodology. Two heterocyclic units grafted to a macrocycle were synthesized with concurrent formation of five chemical bonds in this tandem double cycloaddition process.
Experimental section Published on 24 September 2014. Downloaded on 04/11/2014 17:36:41.
General considerations
a
10c
20
59
70
10d
20
61
76
10e
22
61
74
10f
22
61
71
Isolated yield.
Fig. 1 ORTEP diagram of 10e. For clarity purpose hydrogen atoms are not shown.
The regio- and stereochemical outcome of the cycloaddition reaction was confirmed by a single crystal X-ray analysis of the cycloadduct 11a.18
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Melting points were recorded in capillary tubes and are uncorrected. IR spectra were recorded on an ABB IR-MB3000 series FT-IR spectrophotometer. The 1H NMR (300, 400, 500 MHz), 13C NMR (75 MHz), DEPT, COSY and HMBC spectra were recorded on Bruker (Avance) 300 MHz, 400 MHz and 500 MHz instruments in CDCl3 using TMS as an internal standard. Chemical shifts are given in parts per million and the coupling constants are given in hertz. High resolution mass measurements were carried out using a Micromass Q-ToF instrument using direct inlet mode. Specific rotation was recorded on a RUDOLPH AUTOPOL II, Automatic Polarimeter. Single crystal X-ray diffraction analysis was performed using the Bruker Kappa APEXII area-detector diffractometer. Column chromatography was performed on silica gel (ACME, 100–200 mesh). Routine monitoring of the reaction was done using thin layer chromatography developed on glass plates coated with silica gel-G (ACME) of 25 mm thickness and visualized with iodine. Preparation of monobromo compound 6a–b. To a stirred suspension of potassium carbonate (2.76 g, 20 mmol) in dry DMF (10 ml) was added isatin 4 (1.47 g, 10 mmol), and the solution was stirred at room temperature for 30 min followed by the addition of 1,2-dibromoethane 5a (1.88 g, 10 mmol)/ α,α′-dibromo-p-xylene 5b (2.61 g, 10 mmol) in DMF at room temperature. After the completion of the reaction, as evidenced by TLC, K2CO3 was filtered off, and the solution was extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification of the reaction mixture via column chromatography using hexane–ethyl acetate (8 : 2) furnished the desired N-alkyl/ benzyl bromo isatin in good yields. Preparation of azide fragments 7a–b. To a stirred solution of 1-(2-bromoethyl) indoline-2,3-dione 6a (1 mol)/1-(4-(bromomethyl) benzyl)indoline-2,3-dione 6b (1 mol) in DMSO (60 mL) NaN3 (1.5 mol) was added. The mixture was stirred at room temperature for about 6 h (monitored by TLC). Upon completion of the reaction the mixture was washed with water and extracted with dichloromethane (4 × 20 mL). The combined organic layers were dried (MgSO4) and filtered, concentrated in a vacuum. The azides 7a–b obtained were used without further purification.
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Scheme 7
Table 3
Tandem one-pot 1,3-DC reaction.
Tandem reaction with N-benzyl azido isatin 7b
O-Alkynyl enone
a
Paper
Amino acid
Overall yielda (%) Time Adduct (h) Stepwise Tandem 11a
24
61
72
11b
22
59
69
11c
20
60
73
11d
20
62
70
11e
22
60
77
11f
22
59
71
Isolated yield.
Preparation of O-propargyl glucosyl aldehyde 1. The O-propargylated diacetonide (3 mmol) was dissolved in a mixture of acetic acid and water (3 : 2, 5 mL) and left at room temperature for 12 h. The reaction mixture was then concentrated by
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evaporation and neutralized with saturated sodium bicarbonate and extracted with dichloromethane (4 × 20 mL) and evaporated to give 3-O-benzyl-1,2-O-isopropylidene-α-D-glucofuranose. The product thus obtained was dissolved in THF (10 mL) and a solution of NaIO4 (1.5 eq.) in water (5 mL) was added. The reaction mixture was vigorously stirred for 5 h and was then filtered. The filtrate was extracted twice with dichloromethane and the combined organic fractions were washed with water and dried over sodium sulfate to O-propargyl glucosyl aldehyde 1 as colorless oil in good yield. Synthesis of O-alkynyl enone fragment 3a. To a solution of O-propargyl glucosyl aldehyde 1 (1 g, 4 mmol) in anhydrous THF (15 mL) and triethyl phosphonoacetate (4 mol), LiOH·H2O (4 mmol) was added and the mixture was stirred for 12 h (monitored by TLC). The solvent evaporated under reduced pressure and the residue was dissolved in dichloromethane (2 × 50 mL) and washed with water (2 × 30 mL). The organic layer was dried (Na2SO4) and evaporated under reduced pressure. The residue was chromatographed over silica gel using hexane–ethyl acetate (4 : 1) as the eluent to yield the desired O-alkynyl enone fragment 3a as a colorless oil in good yield. O-Alkynyl enone 3a. Yield: 92% (1.20 g). Colorless oil. 1H NMR (300 MHz, CDCl3): δ 1.28 (t, J = 7.2 Hz, 3H); 1.33 (s, 3H); 1.51 (s, 3H); 1.64 (d, J = 3 Hz, 1H); 2.48 (t, J = 2.1 Hz, 1H); 4.20 (q, J = 7.2 Hz, 2H); 4.21–4.24 (m, 3H); 4.67–4.68 (m, 1H); 4.83 (s, 1H); 5.97 (d, J = 3.9 Hz, 1H); 6.17 (dd, J = 1.5, 15.6 Hz, 1H); 6.93 (dd, J = 5.4, 15.6 Hz, 1H). 13C NMR (75 MHz, CDCl3): 14.2, 26.1, 26.9, 57.7, 60.4, 75.5, 78.6, 79.2, 82.5, 82.6, 112.0, 123.5, 140.8, 166.0. HRMS (EI) exact mass calc. for C15H20O6H: 297.1338 (M + H) found 297.13302. [α]24.3 +7.6 (c 0.2, CHCl3). D Synthesis of O-alkynyl enone fragment 3b. To a solution of O-propargyl glucosyl aldehyde 1 (1 g, 4 mmol) in anhydrous THF (15 mL) and diethyl 2-(4-bromophenyl)-2-oxoethylphosphonate (4 mmol), LiOH·H2O (4 mmol) was added and the mixture was stirred for 12 h (monitored by TLC). The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane (2 × 50 mL) and washed with water (2 × 30 mL). The organic layer was dried (Na2SO4) and evaporated under reduced pressure and the residue was chromatographed over SiO2 using hexane–ethyl acetate (4 : 1) as the
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eluent to yield the desired O-alkynyl enone fragment 3b as a colorless oil in good yield. O-alkynyl enone 3b. Yield: 88% (1.40 g). Colorless oil. 1H NMR (300 MHz, CDCl3): δ 1.28 (s, 3H); 1.45 (s, 3H); 2.42 (t, J = 2.4 Hz, 1H); 4.12 (d, J = 2.4 Hz, 2H); 4.20 (d, J = 3 Hz, 1H); 4.63 (d, J = 3.6 Hz, 1H); 4.91 (d, J = 3.6 Hz, 1H); 5.94 (d, J = 3.9 Hz, 1H); 6.96 (dd, J = 3.9, 15.3 Hz, 1H); 7.16 (dd, J = 1.8, 15.3 Hz, 1H); 7.35–7.41 (m, 2H); 7.85 (d, J = 8.7 Hz, 2H). 13C NMR (75 MHz, CDCl3): 25.2, 25.8, 56.7, 74.6, 77.6, 78.6, 81.4, 81.5, 103.8, 111.1, 125.2, 127.8, 129.1, 134.7, 138.3, 140.3, 187.6 ppm. HRMS (EI) exact mass calc. for C19H19ClO5H: 363.0999 (M + H) found 363.0990. [α]27.1 +9.61(c 0.2, CHCl3). D Preparation of triazole linkers 8a–d. To a solution of O-alkynyl glucosyl enones 3a–b (3.0 mmol) and N-alkylazides 7a–b (3.2 mmol) in THF (15 mL), H2O (15 mL) was added CuSO4·5 H2O (0.7 mmol) and sodium ascorbate (1.5 mmol). The resulting solution was stirred for 12 h at room temperature. The solvent was evaporated under vacuum and the residue was washed with water and brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using hexane–EtOAc (7 : 3) as the eluent. Triazole linker 8a. Yield: 84% (1.4 g). Orange solid. mp 122–124 °C. IR (KBr): 1718, 1732, 2622 cm−1. 1H NMR (300 MHz, CDCl3): δ 1.18 (t, J = 7.2 Hz, 3H); 1.26 (s, 3H); 1.42 (s, 3H); 1.76–1.80 (m, 1H); 3.67 (t, J = 6 Hz, 1H); 3.81 (d, J = 2.7 Hz, 1H); 4.06–4.13 (m, 2H); 4.18–4.24 (m, 1H); 4.46 (d, J = 12.9 Hz, 1H); 4.54–4.60 (m, 2H); 4.62–4.66 (m, 2H); 5.85 (d, J = 3.6 Hz, 1H); 5.96 (dd, J = 1.2, 15.9 Hz, 1H); 6.32 (dd, J = 4.5, 15.9 Hz, 1H); 6.47 (d, J = 8.1 Hz, 1H); 6.99 (t, J = 7.5 Hz, 1H); 7.37 (t, J = 7.5 Hz, 1H); 7.47 (d, J = 7.2 Hz, 1H); 7.55 (s, 1H). 13C NMR (75 MHz, CDCl3): 12.7, 24.1, 24.7, 25.3, 39.2, 46.7, 59.2, 62.3, 66.5, 77.5, 81.2, 81.5, 103.5, 108.5, 110.6, 116.1, 121.3, 122.5, 124.1, 136.9, 140.1, 148.6, 157.1, 164.9, 180.8 ppm. HRMS (EI) exact mass calc. for C25H28N4O8H: 513.1985 (M + H) found 513.1970. [α]24.9 +7.6 (c 0.2, CHCl3). D Triazole linker 8b. Yield: 86% (1.37 g). Orange solid. mp 132–136 °C. IR (KBr): 1722, 1728, 2632 cm−1. 1H NMR (300 MHz, CDCl3): δ 1.35 (s, 3H); 1.52 (s, 3H); 3.93 (d, J = 3 Hz, 1H); 4.21–4.30 (m, 1H); 4.35–4.43 (m, 1H); 4.55 (d, J = 12.9 Hz, 1H); 4.64 (d, J = 3.9 Hz, 1H); 4.70–4.71 (m, 2H); 4.73–4.76 (m, 2H); 5.98 (d, J = 3.6 Hz, 1H); 6.30 (dd, J = 3.9, 15.3 Hz, 1H); 6.55 (d, J = 8.1 Hz, 1H); 7.03 (t, J = 7.5 Hz, 1H); 7.16 (dd, J = 1.8, 15.6 Hz, 1H); 7.43–7.50 (m, 4H); 7.66 (s, 1H); 7.90 (d, J = 8.7 Hz, 2H). 13C NMR (75 MHz, CDCl3): 23.9, 24.5, 38.4, 45.9, 61.6, 77.1, 80.5, 80.6, 102.7, 107.1, 109.9, 115.3, 121.6, 122.4, 123.0, 123.2, 126.7, 127.9, 133.0, 135.9, 137.5, 139.8, 142.6, 147.9, 156.3, 179.9, 186.4 ppm. HRMS (EI) exact mass calc. for C29H27ClN4O7H: 579.1647 (M + H) found 579.1630. [α]25.9 +3.6 D (c 0.2, CHCl3). Triazole linker 8c. Yield: 82% (1.62 g). Orange solid. mp 144–146 °C. IR (KBr): 1710, 1722, 2636 cm−1. 1H NMR (300 MHz, CDCl3): δ 1.19 (t, J = 7.2 Hz, 3H); 1.24 (s, 3H); 1.41 (s, 3H); 3.99 (d, J = 3 Hz, 1H); 4.10 (q, J = 7.2 Hz, 2H); 4.50–4.63 (m, 3H); 4.67–4.70 (m, 1H); 4.85 (s, 2H); 5.43 (d, J = 1.8 Hz, 2H); 5.86 (d, J = 3.6 Hz, 1H); 6.03 (dd, J = 1.5, 15.9 Hz, 1H); 6.67–6.76 (m, 2H); 7.03 (t, J = 7.5 Hz, 1H); 7.18–7.20 (m, 2H);
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Organic & Biomolecular Chemistry
7.26–7.29 (m, 2H); 7.40 (s, 1H); 7.42–7.45 (m, 1H); 7.54 (d, J = 7.2 Hz, 1H). 13C NMR (75 MHz, CDCl3): 14.2, 26.1, 26.7, 43.6, 53.6, 60.4, 64.0, 79.2, 82.7, 83.4, 104.9, 110.8, 112.0, 117.6, 122.8, 123.3, 124.0, 125.5, 128.1, 128.7, 134.6, 135.2, 138.4, 141.2, 144.9, 150.4, 158.2, 166.0, 183.0 ppm. HRMS (EI) exact mass calc. for C31H32N4O8H: 589.2298 (M + H) found 589.2290. [α]25.1 −5.1 (c 0.2, CHCl3). D Triazole linker 8d. Yield: 86% (1.55 g). Orange solid. mp 154–156 °C. IR (KBr): 1714, 1730, 2636 cm−1. 1H NMR (300 MHz, CDCl3): δ 1.27 (s, 3H); 1.44 (s, 3H); 4.08 (d, J = 3 Hz, 1H); 4.52 (d, J = 12.6 Hz, 1H); 4.62 (d, J = 3.6 Hz, 1H); 4.67 (d, J = 12.6 Hz, 1H); 4.82–4.83 (m, 3H); 5.41 (s, 2H); 5.92 (d, J = 3.6 Hz, 1H); 6.65 (d, J = 7.8 Hz, 1H); 6.77 (dd, J = 4.2, 15.3 Hz, 1H); 7.02 (t, J = 7.5 Hz, 1H); 7.10–7.28 (m, 5H); 7.36–7.40 (m, 3H); 7.42 (s, 1H); 7.54 (d, J = 7.5 Hz, 1H); 7.83 (d, J = 8.7 Hz, 2H). 13 C NMR (75 MHz, CDCl3): 26.2, 26.8, 30.9, 43.5, 53.6, 64.0, 79.6, 82.7, 83.3, 104.9, 110.8, 112.2, 117.6, 123.0, 124.0, 125.5, 125.9, 128.1, 128.8, 129.0, 130.1, 134.6, 135.2, 135.6, 138.3, 139.6, 141.8, 144.7, 150.4, 158.2, 183.0, 188.5 ppm. HRMS (EI) exact mass calc. for C35H31ClN4O7H: 655.1960 (M + H) found 655.1966. [α]27.9 −4.6 (c 0.2, CHCl3). D General procedure for the synthesis of macrocycles 10a–f and 11a–f Method A: two step sequential double [3 + 2]cycloaddition reaction. A solution of triazoles 8a–d (0.5 mmol) and L-proline 9a/thiaproline 9b/sarcosine 9c (0.5 mmol) was refluxed in dry toluene (50 mL) under a N2 atmosphere for 8–12 h at 110 °C using the Dean–Stark apparatus. After the completion of reaction as indicated by TLC, toluene was evaporated under reduced pressure. The crude product was washed with water and extracted with ethylacetate (4 × 20 mL). The combined organic layers were dried (MgSO4) and filtered, concentrated in a vacuum. The crude product was purified by column chromatography (hexane–EtOAc, 3 : 7) to give the macrocycles in moderate yield. Method B: one-pot sequential tandem double [3 + 2]cycloaddition reaction. To the O-alkynyl glucosyl enones 3a–b (300 mg, 1 mmol) in dry acetonitrile (10 ml) in N2 atm were added N-alkylazides 7a–b (220 mg, 1 mmol) and secondary amino acid (1 equiv.) followed by diisopropylethylamine (DIPEA) (2.5 equiv.) and CuI (3.0 equiv.).The reaction mixture was stirred for 10–12 h at room temperature. After completion of the reaction as evidenced from TLC, the reaction mixture was refluxed for 12 h. The solvent was evaporated under vacuum and the residue was washed with water and brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using a hexane–EtOAc (3 : 7) mixture as the eluent to give the macrocycles in good yield. Macrocycle 10a. Yield: 76% (0.25 g). White crystalline solid. mp 176–178 °C. IR (KBr): 1381, 1612, 1720, 2644 cm−1. 1H NMR (400 MHz, CDCl3): δ 0.90 (t, J = 7.2 Hz, 3H); 1.32 (s, 3H); 1.48 (s, 3H); 1.73–1.81 (m, 2H); 1.83–1.94 (m, 1H); 1.98–2.05 (m, 1H); 2.10–2.15 (m, 1H); 2.81 (t, J = 6.8 Hz, 1H); 2.95–2.99 (m, 1H); 3.15–3.22 (m, 1H); 3.62–3.70 (m, 2H); 3.87 (d,
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J = 7.2 Hz, 1H); 3.90–3.98 (m, 2H); 4.13–4.18 (m, 1H); 4.30–4.37 (m, 1H); 4.50–4.58 (m, 1H); 4.62 (d, J = 4.0 Hz, 1H); 4.64 (d, J = 12.0 Hz, 1H); 4.73 (d, J = 13.6 Hz, 1H); 4.92 (dd, J = 1.6, 14.0 Hz, 1H); 5.86 (d, J = 4.0 Hz, 1H); 6.88 (d, J = 8.0 Hz, 1H); 7.05 (t, J = 7.6 Hz, 1H); 7.29 (d, J = 7.6 Hz, 1H); 7.35–7.39 (m, 1H); 7.60 (s, 1H); 13C NMR (75 MHz, CDCl3): 13.8, 24.9, 26.2, 26.6, 28.5, 39.5, 46.7, 47.4, 48.6, 55.8, 60.7, 61.2, 71.2, 72.3, 76.6, 79.2, 80.1, 82.0, 103.8, 107.4, 111.6, 122.7, 126.0, 126.1, 126.8, 129.7, 141.7, 173.3, 178.2 ppm. HRMS (EI) exact mass calc. for C29H35N5O7H: 566.2615 (M + H) found 566.2611. [α]26.6 −9.43 D (c 0.2, CHCl3). Macrocycle 10b. Yield: 72% (0.23 g). White crystalline solid. mp 183–186 °C. IR (KBr): 1055, 1378, 1622, 1718, 2634 cm−1. 1 H NMR (500 MHz, CDCl3): δ 1.26 (s, 3H); 1.44 (s, 3H); 1.71–1.80 (m, 2H); 1.84–1.90 (m, 1H); 1.99–2.02 (m, 1H); 2.10–2.13 (m, 1H); 2.68 (t, J = 7.5 Hz, 1H); 3.26–3.30 (m, 2H); 4.04 (t, J = 2.5 Hz, 1H); 4.30 (d, J = 2.0 Hz, 1H); 4.33–4.37 (m, 1H); 4.41–4.44 (m, 2H); 4.51 (d, J = 12.5 Hz, 1H); 4.62 (d, J = 4 Hz, 1H); 4.72–4.75 (m, 1H); 4.91 (d, J = 12.5 Hz, 1H); 4.96 (d, J = 7.0 Hz, 1H); 5.69 (d, J = 4.0 Hz, 1H); 6.57 (d, J = 8.0 Hz, 1H); 6.74 (t, J = 7.5 Hz, 1H); 7.04 (t, J = 7.5 Hz, 1H); 7.08 (d, J = 7.5 Hz, 1H); 7.16–7.19 (m, 2H); 7.21–7.23 (m, 2H); 7.62 (s, 1H). 13 C NMR (75 MHz, CDCl3): 13.1, 25.1, 25.5, 28.0, 39.1, 46.8, 47.1, 49.1, 53.0, 59.4, 61.1, 67.4, 71.2, 76.2, 77.1, 80.3, 81.6, 102.3, 106.2, 110.5, 121.6, 123.6, 124.1, 127.4, 127.6, 128.4, 136.2, 137.6, 141.3, 143.8, 177.0, 200.9 ppm. HRMS (EI) exact mass calc. for C33H34ClN5O6H: 632.2275 (M + H) found 632.2274. [α]28.4 −4.2 (c 0.2, CHCl3). D Macrocycle 10c. Yield: 70% (0.24 g). White crystalline solid. mp 196–198 °C. IR (KBr): 1050, 1388, 1632, 1724, 2638 cm−1. 1 H NMR (300 MHz, CDCl3): δ 0.84 (t, J = 7.2 Hz, 3H); 1.27 (s, 3H); 1.45 (s, 3H); 2.81 (d, J = 6.6 Hz, 1H); 3.03–3.08 (m, 1H); 3.19 (t, J = 9.9 Hz, 1H); 3.32–3.42 (m, 2H); 3.54 (d, J = 9.3 Hz, 1H); 3.68 (d, J = 14.4 Hz, 1H); 3.73–3.79 (m, 1H); 3.82–3.88 (m, 2H); 3.98 (d, J = 9.3 Hz, 1H); 4.32–4.36 (m, 1H); 4.41–4.45 (m, 1H); 4.51–4.61 (m, 1H); 4.61–4.73 (m, 3H); 4.89 (d, J = 13.8 Hz, 1H); 5.87 (d, J = 3.9 Hz, 1H); 6.80 (d, J = 7.8 Hz, 1H); 7.02 (t, J = 7.5 Hz, 1H); 7.31 (d, J = 7.8 Hz, 1H); 7.36 (d, J = 7.2 Hz, 1H); 7.89 (s, 1H). 13C NMR (75 MHz, CDCl3): 12.7, 25.2, 26.0, 34.0, 42.5, 46.7, 51.6, 55.3, 60.2, 60.3, 72.4, 77.4, 78.0, 81.8, 82.9, 103.6, 106.3, 110.6, 122.1, 123.9, 125.0, 129.1, 140.6, 141.5, 170.1, 178.4 ppm. HRMS (EI) exact mass calc. for C28H33N5O7SH: 584.2179 (M + H) found 584.2171. [α]25.5 −6.18 D (c 0.2, CHCl3). Macrocycle 10d. Yield: 76% (0.25 g). White crystalline solid. mp 148–151 °C. IR (KBr): 1055, 1373, 1628, 1730, 2632 cm−1. 1 H NMR (500 MHz, CDCl3): δ 1.26 (s, 3H); 1.44 (s, 3H); 2.93–2.96 (m, 2H); 3.03–3.33 (m, 1H); 3.39–3.40 (m, 1H); 3.54–3.58 (m, 2H); 4.13 (t, J = 2.5 Hz, 1H); 4.25 (d, J = 2.5 Hz, 1H); 4.43–4.47 (m, 2H); 4.54 (d, J = 12.5 Hz, 1H); 4.63–4.64 (m, 2H); 4.76–4.78 (m, 1H); 4.89 (d, J = 12.5 Hz, 1H); 4.98 (d, J = 5.0 Hz, 1H); 5.71 (d, J = 4.0 Hz, 1H); 6.60 (d, J = 7.5 Hz, 1H); 6.77 (t, J = 7.5 Hz, 1H); 6.98 (d, J = 7.0 Hz, 1H); 7.05–7.08 (m, 1H); 7.17–7.21 (m, 4H); 7.66 (s, 1H). 13C NMR (75 MHz, CDCl3): 25.1, 25.6, 31.4, 38.7, 42.3, 44.4, 47.1, 56.3, 61.0, 67.4, 70.7, 78.3, 80.6, 81.3, 102.4, 106.3, 110.6, 122.1, 122.9, 124.0, 126.3,
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127.4, 128.3, 128.8, 135.8, 137.5, 140.9, 143.5, 176.9, 198.0 ppm. HRMS (EI) exact mass calc. for C32H32ClN5O6SNa: 672.1660 (M+) found 672.1661. [α]25.8 −5.04 (c 0.2, CHCl3). D Macrocycle 10e. Yield: 74% (0.23 g). White crystalline solid. mp 144–146 °C. IR (KBr): 1044, 1380, 1622, 1731, 2632 cm−1. 1 H NMR (400 MHz, CDCl3): δ 0.93 (t, J = 7.2 Hz, 3H); 1.32 (s, 3H); 1.49 (s, 3H); 2.08 (s, 3H); 3.21–3.25 (m, 1H); 3.27 (t, J = 7.2 Hz, 1H); 3.57 (t, J = 7.2 Hz, 1H); 3.62–3.70 (m, 3H); 3.87–3.95 (m, 1H); 3.97 (d, J = 3.2 Hz, 1H); 4.15 (t, J = 3.2 Hz, 1H); 4.34–4.41 (m, 1H); 4.54–4.61 (m, 1H); 4.64–4.65 (m, 1H); 4.66 (d, J = 13.2 Hz, 1H); 4.75 (d, J = 13.2 Hz, 1H); 4.92 (dd, J = 1.2, 14.0 Hz, 1H); 5.87 (d, J = 4.0 Hz, 1H); 6.86, (d, J = 8.0 Hz, 1H); 7.05–7.09 (m, 1H); 7.14–7.16 (m, 1H); 7.32–7.36 (m, 1H); 7.70 (s, 1H). 13C NMR (75 MHz, CDCl3): 12.8, 25.1, 25.6, 34.3, 38.1, 38.3, 46.4, 53.6, 59.5, 59.7, 60.2, 72.1, 78.3, 80.5, 81.2, 102.9, 106.1, 110.5, 122.1, 124.4, 125.2, 125.6, 128.5, 140.4, 141.9, 170.9, 177.8 ppm. HRMS (EI) exact mass calc. for C27H33N5O7H: 540.2458 (M + H) found 540.2455. [α]26.3 −7.84 D (c 0.2, CHCl3). Macrocycle 10f. Yield: 71% (0.22 g). White crystalline solid. mp 155–157 °C. IR (KBr): 1048, 1376, 1632, 1731, 2624 cm−1. 1 H NMR (500 MHz, CDCl3): δ 1.26 (s, 3H); 1.44 (s, 3H); 2.01 (s, 3H); 3.37–3.47 (m, 2H); 3.52–3.59 (m, 1H); 3.61–3.63 (m, 1H); 4.10 (t, J = 2.5 Hz, 1H); 4.16 (d, J = 3.0 Hz, 1H); 4.46–4.48 (m, 2H); 4.53–4.54 (m, 1H); 4.58 (d, J = 13.0 Hz, 1H); 4.60 (d, J = 4.0 H, 1H); 4.79–4.81 (m, 1H); 4.84 (d, J = 13.0 Hz, 1H); 5.71 (d, J = 4.0 Hz, 1H); 6.66 (d, J = 7.5 Hz, 1H); 6.78 (t, J = 7.5 Hz, 1H); 6.92–6.93 (m, 1H); 7.09–7.12 (m, 1H); 7.19–7.24 (m, 2H); 7.48 (d, J = 8.5 Hz, 2H); 7.63 (s, 1H). 13C NMR (75 MHz, CDCl3): 24.3, 24.8, 33.1, 37.5, 38.4, 45.8, 52.0, 57.8, 59.5, 71.9, 79.1, 79.6, 80.2, 101.5, 105.5, 109.7, 121.5, 123.0, 123.4, 125.2, 126.7, 127.8, 128.2, 134.9, 136.9, 140.0, 142.3, 176.4, 198.7 ppm. HRMS (EI) exact mass calc. for C31H32ClN5O6H: 606.2119 (M + H) found 606.2112. [α]25.4 −6.59 (c 0.2, CHCl3). D Macrocycle 11a. Yield: 72% (0.23 g). White crystalline solid. mp 166–168 °C. IR (KBr): 1038, 1389, 1632, 1718, 2639 cm−1. 1 H NMR (500 MHz, CDCl3): δ 0.73 (t, J = 7.5 Hz, 3H); 1.24 (s, 3H); 1.47 (s, 3H); 1.63 (d, J = 6.5 Hz, 1H); 1.69–1.77 (m, 1H); 1.79–1.87 (m, 2H); 2.16–2.21(m, 1H); 2.58–2.63 (m, 1H); 2.68–2.71 (m, 1H); 3.12–3.16 (m, 2H); 3.54–3.62 (m, 2H); 4.16–4.17 (m, 1H); 4.24–4.27 (m, 1H); 4.44 (d, J = 14.0 Hz, 1H); 4.56 (d, J = 14.0 Hz, 1H); 4.62–4.66 (m, 2H); 4.84 (d, J = 14.0 Hz, 1H); 5.07 (d, J = 14.0 Hz, 1H); 5.71 (d, J = 14.0 Hz, 1H); 5.78 (d, J = 4.0 Hz, 1H); 6.89 (s, 1H); 6.92 (t, J = 7.5 Hz, 1H); 7.07 (d, J = 8.0 Hz, 1H); 7.11 (d, J = 7.5 Hz, 1H); 7.15 (d, J = 7.5 Hz, 1H); 7.20–7.26 (m, 2H); 7.33 (t, J = 8.0 Hz, 1H); 7.56 (d, J = 8.0 Hz, 1H). 13C NMR (75 MHz, CDCl3): 12.8, 25.0, 25.5, 26.1, 29.4, 42.8, 47.3, 47.8, 53.4, 57.9, 59.4, 59.9, 71.1, 71.5, 78.2, 79.5, 83.4, 103.5, 107.9, 110.7, 121.0, 122.4, 125.3, 125.8, 126.6, 127.7, 128.4, 128.6, 131.0, 134.0, 135.9, 141.7, 142.0, 171.5, 177.1 ppm. HRMS (EI) exact mass calc. for C35H39N5O7H: 642.2928 (M + H) found 642.2926. [α]28.8 −8.74 (c 0.2, CHCl3). D Macrocycle 11b. Yield: 69% (0.22 g). White crystalline solid. mp 170–172 °C. IR (KBr): 1050, 1398, 1623, 1716, 2663 cm−1. 1 H NMR (300 MHz, CDCl3): δ 1.27 (s, 3H); 1.47 (s, 3H); 2.20–2.34 (m, 2H); 2.59–2.64 (m, 1H); 2.75–2.76 (m, 1H);
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2.80–2.85 (m, 1H); 3.17 (d, J = 4.5 Hz, 1H); 3.26–3.30 (m, 1H); 3.98–4.03 (m, 2H); 4.33–4.35 (m, 1H); 4.42–4.49 (m, 2H); 4.54 (d, J = 14.1 Hz, 1H); 4.65 (d, J = 3.9 Hz, 1H); 4.90 (d, J = 14.1 Hz, 1H); 5.14 (d, J = 14.1 Hz, 1H); 5.65 (d, J = 14.1 Hz, 1H); 5.75 (d, J = 3.9 Hz, 1H); 5.91 (s, 1H); 6.50–6.56 (m, 3H); 6.87 (d, J = 7.5 Hz, 1H); 6.98–7.00 (m, 4H); 7.07–7.12 (m, 2H); 7.29–7.38 (m, 2H); 7.73 (d, J = 7.8 Hz, 1H). 13C NMR (75 MHz, CDCl3): 25.9, 26.2, 28.6, 30.8, 42.8, 47.5, 49.4, 53.2, 57.3, 59.7, 70.0, 71.8, 79.2, 80.7, 82.1, 103.1, 107.0, 111.1, 121.2, 122.2, 124.1, 126.4, 127.1, 127.6, 127.9, 128.3, 131.7, 135.4, 136.5, 142.4, 176.7, 198.4 ppm. HRMS (EI) exact mass calc. for C39H38ClN5O6H: 708.2589 (M + H) found 708.2584. [α]26.4 −6.6 D (c 0.2, CHCl3). Macrocycle 11c. Yield: 73% (0.24 g). White crystalline solid. mp 182–184 °C. IR (KBr): 1034, 1367, 1633, 1738, 2665 cm−1. 1 H NMR (500 MHz, CDCl3): δ 0.74 (t, J = 7.0 Hz, 3H); 1.26 (s, 3H); 1.46 (s, 3H); 1.78 (d, J = 2.1 Hz, 1H); 2.08–2.86 (m, 2H); 3.05–3.09 (m, 1H); 3.31–3.32 (m, 1H); 3.32 (d, J = 8.5 Hz, 1H); 3.48–3.55 (m, 2H); 3.38 (d, J = 8.5 Hz, 1H); 3.96–4.00 (m, 1H); 4.48 (d, J = 4.0 Hz, 1H); 4.50–4.53 (m, 1H); 4.61 (d, J = 9.5 Hz, 1H); 4.64 (d, J = 9.5 Hz, 1H); 4.71 (d, J = 4.0 Hz, 1H); 4.72–4.75 (m, 1H); 5.12 (d, J = 13.5 Hz, 1H); 5.67 (d, J = 13.5 Hz, 1H); 5.81 (d, J = 4.0 Hz, 1H); 6.92 (s, 1H); 6.95 (t, J = 7.5 Hz, 1H); 7.08 (d, J = 7.5 Hz, 1H); 7.11 (d, J = 7.5 Hz, 1H); 7.16–7.20 (m, 2H); 7.22–7.23 (m, 1H); 7.30–7.34 (m, 1H); 7.58–7.59 (m, 1H). 13C NMR (75 MHz, CDCl3): 12.8, 25.5, 26.0, 34.8, 42.0, 43.3, 50.1, 53.6, 57.2, 59.5, 59.8, 71.3, 73.6, 76.5, 79.0, 81.7, 103.6, 107.3, 110.8, 121.3, 121.5, 123.4, 125.7, 126.6, 127.4, 128.5, 129.0, 131.5, 133.9, 135.6, 142.0, 142.1, 169.5, 177.0 ppm. HRMS (EI) exact mass calc. for C34H37N5O7SH: 660.2492 (M + H) found 660.2490. [α]25.4 −4.38 (c 0.2, CHCl3). D Macrocycle 11d. Yield: 70% (0.23 g). White crystalline solid. mp 202–204 °C. IR (KBr): 1048, 1387, 1622, 1738, 2676 cm−1. 1 H NMR (300 MHz, CDCl3): δ 1.27 (s, 3H); 1.48 (s, 3H); 2.77–2.78 (m, 1H); 2.84–2.91 (m, 1H); 2.96 (d, J = 9.0 Hz, 1H); 3.03–3.08 (m, 1H); 3.20 (d, J = 4.8 Hz, 1H); 3.46 (s, 2H); 4.13 (d, J = 13.8 Hz, 1H); 4.23–4.30 (m, 1H); 4.45–4.55 (m, 3H); 4.67 (d, J = 3.9 Hz, 1H); 4.89 (d, J = 13.8 Hz, 1H); 5.18 (d, J = 14.1 Hz, 1H); 5.70 (d, J = 14.1 Hz, 1H); 5.73 (d, J = 3.9 Hz, 1H); 6.35 (s, 1H); 6.59 (t, J = 7.5 Hz, 1H); 6.80 (d, J = 7.2 Hz, 3H); 6.94 (d, J = 7.8 Hz, 1H); 7.02–7.09 (m, 4H); 7.26 (d, J = 7.8 Hz, 1H); 7.40 (d, J = 7.2 Hz, 1H); 7.69 (d, J = 8.1 Hz, 1H). 13C NMR (75 MHz, CDCl3): 25.8, 26.2, 32.6, 41.6, 43.0, 45.0, 53.3, 59.4, 68.5, 71.8, 76.2, 78.2, 80.1, 81.5, 103.3, 107.1, 111.1, 121.7, 122.5, 122.8, 125.6, 126.6, 127.2, 127.5, 127.8, 128.3, 128.7, 131.5, 134.6, 135.5, 136.1, 137.6, 141.2, 142.1, 176.7, 195.3 ppm. HRMS (EI) exact mass calc. for C38H36ClN5O6SH: 726.2153 (M + H) found 726.2153. [α]28.7 −9.2 (c 0.2, CHCl3). D Macrocycle 11e. Yield: 77% (0.24 g). White crystalline solid. mp 192–196 °C. IR (KBr): 1032, 1376, 1632, 1721, 2654 cm−1. 1 H NMR (300 MHz, CDCl3): δ 0.79 (t, J = 7.2 Hz, 3H); 1.24 (s, 3H); 1.41 (s, 3H); 1.48 (d, J = 5.1 Hz, 1H); 2.06 (s, 3H); 2.98–3.06 (m, 1H); 3.14 (d, J = 4.8 Hz, 1H); 3.29 (t, J = 8.4 Hz, 1H); 3.46 (t, J = 8.4 Hz, 1H); 3.56–3.68 (m, 2H); 4.25–4.30 (m, 1H); 4.44–4.54 (m, 2H); 4.62–4.67 (m, 2H); 4.87 (d, J = 14.4 Hz, 1H); 5.06 (d, J = 14.1 Hz, 1H); 5.73–5.79 (m, 2H); 6.92–7.11
Org. Biomol. Chem.
Organic & Biomolecular Chemistry
(m, 5H); 7.21–7.33 (m, 3H), 7.51 (d, J = 7.8 Hz, 1H). 13C NMR (75 MHz, CDCl3): 12.9, 25.6, 26.1, 34.5, 38.6, 42.8, 53.4, 55.1, 58.9, 59.5, 59.8, 73.2, 77.5, 79.4, 83.3, 103.6, 107.8, 110.8, 121.7, 122.5, 124.2, 125.7, 126.6, 127.6, 128.4, 128.6, 130.7, 134.4, 135.9, 141.5, 142.1, 170.1, 177.5 ppm. HRMS (EI) exact mass calc. for C33H37N5O7H: 616.2771 (M + H) found 616.2772. [α]25.8 −5.04 (c 0.2, CHCl3). D Macrocycle 11f. Yield: 71% (0.22 g). White crystalline solid. mp 188–190 °C. IR (KBr): 1040, 1392, 1633, 1740, 2677 cm−1. 1 H NMR (300 MHz, CDCl3): δ 1.26 (s, 3H); 1.47 (s, 3H); 2.12 (s, 3H); 3.01–3.10 (m, 2H); 3.45 (t, J = 8.7 Hz, 1H); 3.59 (t, J = 8.7 Hz, 1H); 4.06–4.10 (m, 1H); 4.46–4.51 (m, 4H); 4.65 (d, J = 3.3 Hz, 1H); 4.99 (d, J = 14.1 Hz, 1H); 5.10 (d, J = 14.1 Hz, 1H); 5.75–5.78 (m, 2H); 6.52–6.57 (m, 1H); 6.62–6.64 (m, 2H); 6.91 (d, J = 8.1 Hz, 1H); 6.99–7.01 (m, 2H); 7.01–7.08 (m, 3H); 7.38–7.45 (m, 3H); 7.66–7.67 (m, 1H). 13C NMR (75 MHz, CDCl3): 25.9, 26.2, 34.5, 38.4, 42.5, 53.2, 57.9, 59.2, 73.7, 76.2, 77.8, 79.7, 82.7, 103.4, 107.2, 111.0, 121.7, 122.6, 124.2, 124.9, 126.4, 127.2, 127.4, 127.6, 128.3, 131.0, 134.7, 135.9, 136.3, 137.5, 141.2, 142.2, 177.3, 196.2 ppm. HRMS (EI) exact mass calc. for C37H36ClN5O6H: 682.2432 (M + H) found 682.2310. [α]28.4 −4.2 (c 0.2, CHCl3). D
Acknowledgements The authors RP, SP and RR thank DST-FIST program for the NMR facility. The authors wish to thank Ms V. Sabari for single crystal X-ray data. RP thanks CSIR New Delhi for the award of SRF. RR thanks UGC, New Delhi for BSR faculty fellowship.
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